American journal of respiratory medicine : drugs, devices, and other interventions最新文献

Unlabelled: Clarithromycin is an orally active, advanced-generation macrolide that has been reformulated as an extended-release tablet (Biaxin) XL Filmtab allowing convenient once-daily administration. The reformulation is intended to improve patient compliance and the tolerability of the drug. Although maximum plasma clarithromycin concentrations are lower and reached later with the extended-release tablets than with the immediate-release tablets, the two formulations are bioequivalent with respect to the area under the plasma concentration-time curve. Bioequivalence is also achieved between the formulations for the microbiologically active metabolite, 14-hydroxy-clarithromycin. Two randomized trials in patients with acute exacerbations of chronic bronchitis (AECB) showed that a 7-day course of clarithromycin extended-release 1000 mg once daily produced clinical cure rates of 83% and 85% and bacteriologic cure rates of 86% and 92% at the test-of-cure study visit. Similar rates of cure were achieved with a 7-day course of twice-daily clarithromycin immediate-release and with a 10-day course of twice-daily amoxicillin/clavulanic acid.A 7-day course of clarithromycin extended-release 1000 mg once daily produced clinical and bacteriologic cure rates of 88% and 86%, respectively, in patients with community-acquired pneumonia (CAP). Similar cure rates were achieved in recipients of once-daily levofloxacin in the same trial. In patients with acute maxillary sinusitis, a 14-day course of either once-daily clarithromycin extended-release or twice-daily clarithromycin immediate-release produced statistically equivalent clinical cure rates of 85% and 79%, respectively. Both treatment groups achieved similar rates of radiographic success and resolution of sinusitis. Recent results indicate that clarithromycin extended-release 500 mg once daily for 5 days is also effective in the treatment of patients with streptococcal pharyngitis/tonsillitis and in the treatment of AECB. The most frequently reported drug-related events with clarithromycin extended-release were abnormal taste (7% incidence), diarrhea (6%) and nausea (3%). Most adverse drug reactions were of a mild and transient nature. In comparative clinical trials, clarithromycin extended-release had an improved gastrointestinal tolerability profile compared with the immediate-release formulation. In addition, clarithromycin extended-release was better tolerated than amoxicillin/clavulanic acid and as well tolerated as levofloxacin. Further studies are required to assess the cost-effectiveness ratio of clarithromycin relative to comparator antibacterial agents.

Conclusion: Clarithromycin extended-release is an effective treatment for AECB, CAP, acute maxillary sinusitis, and pharyngitis (although not approved for the latter in the US), and is administered in a convenient dosage regimen that has the potential to encourage good compliance. The reformulation modulat

Cystic fibrosis (CF), is an autosomal recessive disease frequently seen in the Caucasian population. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF is characterized by enhanced airway Na(+) absorption, mediated by epithelial Na(+) channels (ENaC), and deficient Cl(-) transport. In addition, other mechanisms may contribute to the pathophysiological changes in the CF lung, such as defective regulation of HCO(3)(-) secretion. In other epithelial tissues, epithelial Na(+) conductance is either increased (intestine) or decreased (sweat duct) in CF. CFTR is a cyclic AMP-regulated epithelial Cl(-) channel, and appears to control the activity of several other transport proteins. Accordingly, defective epithelial ion transport in CF is likely to be a combination of defective Cl(-) channel function and impaired regulator function of CFTR, which in turn is linked to impaired mucociliary clearance and development of chronic lung disease. As the clinical course of CF is determined primarily by progressive lung disease, novel pharmacological strategies for the treatment of CF focus on correction of the ion transport defect in the airways. In recent years, it has been demonstrated that activation of purinergic receptors in airway epithelia by extracellular nucleotides (adenosine triphosphate/uridine triphosphate) has beneficial effects on mucus clearance in CF. Activation of the dominant class of metabotropic purinergic receptors, P2Y(2) receptors, appears to have a 2-fold benefit on ion transport in CF airways; excessive Na(+) absorption is attenuated, most likely by inhibition of the ENaC and, simultaneously, an alternative Ca(2+)-dependent Cl(-) channel is activated that may compensate for the CFTR Cl(-) channel defect. Thus activation of P2Y(2) receptors is expected to lead to improved hydration of the airway surface liquid in CF. Furthermore, purinergic activation has been shown to promote other components of mucociliary clearance such as ciliary beat frequency and mucus secretion. Clinical trials are under way to test the effect of synthetic purinergic compounds, such as the P2Y(2) receptor agonist INS37217, on the progression of lung disease in patients with CF. Administration of these compounds alone, or in combination with other drugs that inhibit accelerated Na(+) transport and help recover or increase residual activity of mutant CFTR, is most promising as successful therapy to counteract the ion transport defect in the airways of CF patients.

Severe community-acquired pneumonia (CAP) is a life-threatening condition that requires intensive care unit (ICU) admission. Clinical presentation is characterized by the presence of respiratory failure, severe sepsis, or septic shock. Severe CAP accounts for approximately 5-35% of hospital-treated cases of pneumonia with the majority of patients having underlying comorbidities. The most common pathogens associated with this disease are Streptococcus pneumoniae, Legionella spp., Haemophilus influenzae, and Gram-negative enteric rods. Microbial investigation is probably helpful in the individual case but is likely to be more useful for defining local antimicrobial policies. The early and rapid initiation of empiric antimicrobial treatment is critical for a favorable outcome. It should include intravenous beta-lactam along with either a macrolide or a fluoroquinolone. Modifications of this basic regimen should be considered in the presence of distinct comorbid conditions and risk factors for specific pathogens. Other promising nonantimicrobial new therapies are currently being investigated. The assessment of severity of CAP helps physicians to identify patients who could be managed safely in an ambulatory setting. It may also play a crucial role in decisions about length of hospital stay and time of switching to oral antimicrobial therapy in different groups at risk. The most important adverse prognostic factors include advancing age, male sex, poor health of patient, acute respiratory failure, severe sepsis, septic shock, progressive radiographic course, bacteremia, signs of disease progression within the first 48-72 hours, and the presence of several different pathogens such as S. pneumoniae, Staphylococcus aureus, Gram-negative enteric bacilli, or Pseudomonas aeruginosa. However, some important topics of severity assessment remain controversial, including the definition of severe CAP. Prediction rules for complications or death from CAP, although far from perfect, should identify the majority of patients with severe CAP and be used to support decision-making by the physician. They may also contribute to the evaluation of processes and outcomes of care for patients with CAP.

Corticosteroids are the mainstay of treatment for sarcoidosis. Although the indications for medical therapy of sarcoidosis are controversial, standard therapy for symptomatic, progressive disease consists of corticosteroids. The British Thoracic Society concluded, with respect to systemic corticosteroids for the treatment of sarcoidosis, that some patients required no treatment, some required prednisone for control of symptoms, and others, with persistent disease, appeared to benefit from long-term corticosteroid therapy. Inhaled budesonide can be an effective treatment for lung sarcoidosis, with few adverse effects, when used in combination with oral systemic corticosteroids such as deflazacort administered in a tapered regimen for 6 months. A randomized controlled trial has also demonstrated the efficacy of 3 months of treatment with oral prednisolone in a tapered regimen followed by inhaled budesonide for 15 months in patients with early stage pulmonary sarcoidosis.Alternative drugs are required in chronic resistant sarcoidosis and/or in conditions where systemic corticosteroids are contraindicated. Immunosuppressive agents (chlorambucil, cyclophosphamide, methotrexate, cyclosporine, azathioprine), anticytokine agents (thalidomide, pentoxifylline), antimalarials (chloroquine, hydroxychloroquine), melatonin and monoclonal antibody (infliximab) have been used in such situations. Chlorambucil and cyclophosphamide have been used in anecdotal cases of pulmonary sarcoidosis as corticosteroid-sparing agents. However, their toxicity and neoplastic potential recommend prudence in patient selection. A comparison between combination therapy with cyclosporine and prednisone and prednisone alone has shown an increased prevalence of serious adverse effects with combined therapy with no between-group differences in treatment efficacy. The cost and toxicity of cyclosporine limit its use to patients in whom its efficacy has been proven. In patients with chronic or refractory disease, methotrexate, usually administered once a week as a single oral dose for at least 2 years, has resulted in a significant improvement in respiratory function, chest radiographs and extrapulmonary manifestations. In most patients, this treatment enabled discontinuation of corticosteroids. Azathioprine may be effective as a corticosteroid-sparing agent in the long-term treatment of sarcoidosis. The combination of prednisolone and azathioprine over a period of 2 years has induced long-lasting remission in patients with resistant sarcoidosis. Thalidomide at low doses is effective in selected cases of sarcoidosis with cutaneous and mild pulmonary involvement. Pentoxifylline alone or combined with low doses of corticosteroids has achieved significant improvement in respiratory function in patients with pulmonary sarcoidosis. Chloroquine and hydroxychloroquine have been shown to have a specific effect in cutaneous manifestations, neurological involvement and hypercalcemia associated

The nuclear factor kappa B (NF-kappaB) transcription factor plays a key role in the induction of pro-inflammatory gene expression, leading to the synthesis of cytokines, adhesion molecules, chemokines, growth factors and enzymes. Results of studies in in vitro and in vivo models of inflammation and malignancy have also suggested central roles for NF-kappaB in programmed cell death, or apoptosis. NF-kappaB plays a central role in a variety of acute and chronic inflammatory diseases. In the common lung diseases associated with a significant inflammatory component such as severe sepsis, acute lung injury, acute respiratory distress syndrome, cystic fibrosis and asthma, the pathogenic roles of NF-kappaB have been extensively investigated. In COPD, activation of NF-kappaB has been implicated in disease pathogenesis but its exact role is less clearly demonstrable in this heterogeneous patient population. However, the principal risk factor for COPD, cigarette smoking, is strongly associated with NF-kappaB activation. Activation of NF-kappaB has been demonstrated in mineral dust diseases and probably plays a role in the pathogenesis of these chronic illnesses. NF-kB also plays a variety of roles in lung cancer including resistance to chemotherapy, inhibition of tumorigenesis and inducing expression of antiapoptotic genes. The complex NF-kappaB pathway offers a variety of potential molecular targets for chemotherapeutic intervention. A variety of agents aimed at modulating NF-kappaB activity are in various stages of investigation.

Emotional factors are an obstacle in the diagnosis and management of asthma. This review discusses three problem patterns: negative emotions in relatively normal patients with asthma; patients presenting possible functional symptoms and; patients presenting asthma in conjunction with psychiatric deviations. Negative emotions influence the symptoms and management of asthma, even in relatively normal patients. Psychogenic symptoms appear normal, but culminate in functional symptoms in a minority of patients. Diagnosing and treating asthma in patients with comorbid asthma and psychiatric symptoms is very difficult. On the one hand, treating asthma may often be just treating the emotions. On the other hand, negative emotions make the treatment of asthma guesswork. Physicians should estimate emotional influences in their patients' symptoms for an optimal evaluation of medication efficacy. Assessment and analysis of emotional factors surrounding exacerbations seems essential, e.g. emotional precipitants of asthma and asthma-evoked negative emotions. Moreover, patients should be informed about stress-induced breathlessness and the consequences of overuse of bronchodilators. When patients present with atypical symptoms, or do not properly respond to asthma medication, functional symptoms should be suspected. Psychiatric analysis may often lead to the conclusion that symptoms have a functional basis. In patients with comorbid asthma and anxiety disorders, asthma should be the focus for treatment since difficult-to-control asthma often causes anxiety problems in the first place. Moreover, panic-like symptoms in asthma are often related to sudden onset asthma exacerbations. However, in patients with comorbid asthma and depression, depression should become the focus of treatment. The reason is that optimal treatment of depressive asthmatics is probably impossible. Special issues include specific problems with children, compliance problems, and physicians' dilemmas regarding the simultaneous treatment of asthma and psychiatric symptoms.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a prevalent disorder associated with substantial cardiovascular and neurobehavioral morbidity. Yet this is a disorder for which there are no widely effective pharmacotherapies. The pathophysiology of obstructive sleep apnea namely, normal respiration in waking with disordered breathing only in sleep, suggests that this disorder should be readily amenable to drug therapy. Over the past 10 years, we have gained tremendous insight into the neurochemical mechanisms involved in state-dependent control of respiration. It is apparent from this work that there are many potential avenues for pharmacotherapies, including several seemingly conflicting directions for serotonergic therapies. Serotonin delivery is reduced to upper airway dilator motor neurons in sleep, and this contributes, at least in part, to sleep-related reductions in dilator muscle activity and upper airway obstruction. The dilator motor neuron post-synaptic serotonin receptors are 5-HT(2A) and 5-HT(2C) subtypes, and in adults the presynaptic 5-HT receptor in motor nuclei is 5-HT(1B), an inhibitory receptor. Serotonin receptors are also found within central respiratory neuronal groups, and these receptor subtypes include 5-HT(1A) (inhibitory) and 5-HT(2) receptors. Peripherally, stimulation of 5-HT(2A), 5-HT(2C) and 5-HT(3) receptor subtypes have an inhibitory effect on respiration via action at the nodose ganglion. Many of these receptor subtypes and their signal transduction pathways may be affected by oxidative stress in obstructive sleep apnea. These alterations will make finding drug therapies for sleep apnea more challenging, but not insurmountable. Future directions are suggested for elucidating safe, well-tolerated serotonergic drugs for this disorder. Tryptophan was one of the first serotonergic drugs tested for OSAHS. This drug was withdrawn from the market as a result of reports linking tryptophan use with eosinophilic myalgia syndrome and life-threatening pulmonary hypertension. Newer drugs with serotonergic activity tested in persons with sleep-disordered breathing include buspirone, fluoxetine and paroxetine. Trials are presently being conducted to evaluate the effects of 5-HT(2A) and 5-HT(3) antagonists on OSAHS. Many of the drugs tested have not shown significant improvement in sleep apnea. However, with continued effort to elucidate the pharmacology of neurochemical control of state-dependent changes in respiratory control, the availability of pharmacological therapy for this disorder is not too far away.

For several years there has been discussion of whether first-line pharmacological treatment of allergic rhinitis should be antihistamines or intranasal corticosteroids. No well documented, clinically relevant differences seem to exist for individual nonsedating antihistamines in the treatment of allergic rhinitis. Likewise, the current body of literature does not seem to favor any specific intranasal corticosteroid. When comparing efficacy of antihistamines and intranasal corticosteroids in allergic rhinitis, present data favor intranasal corticosteroids. Interestingly, data do not support antihistamines as superior in treating conjunctivitis associated with allergic rhinitis. Safety data from comparative studies in allergic rhinitis do not indicate differences between antihistamines and intranasal corticosteroids. Combining antihistamines and intranasal corticosteroids in the treatment of allergic rhinitis does not provide additional beneficial effects to intranasal corticosteroids alone. Considering present data, intranasal corticosteroids seem to offer superior relief in allergic rhinitis, when compared with antihistamines.

COPD, encompassing both chronic bronchitis and emphysema, usually results from exposure to tobacco smoke. Smoking causes infiltration of the airways with leukocytes, an imbalance between proteases and their naturally occurring inhibitors and local cytokine secretion in the lung, which leads to airway inflammation and alveolar destruction. Corticosteroids have a range of anti-inflammatory actions, particularly inhibition of cytokine secretion, which suggests that they may be effective in COPD. However, data from the highest quality studies available do not show any evidence of significant improvement in symptoms of patients with COPD treated with systemic corticosteroids.A meta-analysis found that about 10% of patients with stable COPD showed an improvement in lung function following treatment with short-term systemic corticosteroids compared with placebo. Exercise capacity in patients with COPD was evaluated in four studies, only one of which found a significant improvement with oral corticosteroids compared with placebo. Long-term systemic corticosteroid treatment in patients with stable COPD has not been found to alter the rate of decline in FEV(1). Although systemic corticosteroids are associated with a range of adverse effects, the data do not allow precise quantification of their contribution to morbidity. However, studies show an increased risk of osteoporosis in COPD. Recent studies have also found an association between oral corticosteroid administration and mortality in patients with stable COPD, but it is not clear if this is a cause and effect relationship. Current data do not support long-term administration of systemic corticosteroids to all patients with stable COPD. Results of studies suggest that short-term oral corticosteroid administration may identify a sub-population of patients with COPD who may benefit through a reduction in the decline in FEV(1) and better control of symptoms by long-term administration of inhaled corticosteroids; these findings need to be tested by further research.

The incidence of lower respiratory tract infection (LRTI) in women of child-bearing age is approximately 64 per 1000 population. The spectrum of illness ranges from acute bronchitis, which is very common, through influenza virus infection and exacerbations of underlying lung disease, to pneumonia, which, fortunately is uncommon (<1.5% LRTI), but can be severe. Acute bronchitis is generally mild, self-limiting and usually does not require antibacterial therapy. Influenza virus infection in pregnant women has been recently related to increased hospitalization for acute cardiorespiratory conditions. At present, the safety of the newer neuraminidase inhibitors for the treatment of influenza virus infection has not been established in pregnancy and they are not routinely recommended. In influenza virus infection complicated by pneumonia, antibacterial agents active against Staphylococcus aureus and Streptococcus pneumoniae superinfection should be used. There are few data on infective complications of asthma or COPD in pregnancy. The latter is rare, as patients with COPD are usually male and aged over 45 years. Management is the same as for nonpregnant patients. The incidence and mortality of pneumonia in pregnancy is similar to that in nonpregnant patients. Infants born to pregnant patients with pneumonia have been found to be born earlier and weigh less than controls. Risk factors for the development of pneumonia include anemia, asthma and use of antepartum corticosteroids and tocolytic agents. Based on the few available studies, the main pathogens causing pneumonia are S. pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae and viruses. Beta-Lactam and macrolide antibiotics therefore remain the antibiotics of choice in terms of both pathogen coverage and safety in pregnancy. In HIV-infected pregnant patients, recurrent bacterial pneumonia, but not Pneumocystis carinii pneumonia (PCP), is more common than in nonpregnant patients. Trimethoprim/sulfamethoxazole (cotrimoxazole) has not definitely been associated with adverse clinical outcomes despite theoretical risks. Currently it is still the treatment of choice in PCP, where mortality remains high. In conclusion, there are few data specifically related to pregnant women with different types of LRTI. Where data are available, no significant differences compared with nonpregnant patients have been identified. In considering the use of any therapeutic agent or investigation in pregnant patients with LRTI, safety aspects must be carefully weighed against potential benefit. Otherwise, management strategies should not differ from those for nonpregnant patients. Further research in this area is warranted.